Alterations in the structural and functional states of chromatin are involved in the pathogenesis of a variety of diseases. The biochemical and enzymatic processes that catalyze the insertion and elimination of the post-translational modifications on the nucleosomes have become the subject of research as potential targets for the so-called epigenetic therapies (Urdinguio R G, Sanchez-Mut J V, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8:1056-1072, 2009). The discovery of an increasing number of histone demethylases has highlighted the dynamic nature of the regulation of histone methylation, a key chromatin modification that is involved in eukaryotic genome and gene regulation. Histone lysine demethylases represent very attractive targets for epigenetic drugs and are gaining increasing attention. A lysine can be mono-, di-, and tri-methylated. Each modification on the same amino acid can specifically exert different biological effects. The recent discovery of histone lysine demethylases has revealed two types of enzymatic mechanisms (Anand R, Marmorstein R. Structure and mechanism of lysine-specific demethylase enzymes. J. Biol. Chem. 282:35425-35429, 2007). The iron-dependent enzymes can demethylate lysine side chains in all three methylation states and many demethylases in this family have now been characterized. Conversely, the oxidative chemistry that underlies the function of flavin-dependent histone demethylases makes it impossible for these enzymes to act on a trimethylated lysine and restricts their activity to mono- and di-methylated substrates. Mammals contain two flavoenzyme demethylases: LSD1 and LSD2. LSD1 was the first discovered histone demethylase and is typically (but not always) associated with the co-repressor protein CoREST. LSD1/CoREST can associate to histone deacetylases 1/2 (HDAC1/2) forming a multienzyme unit that is recruited by many chromatin complexes that are typically involved in gene repression regulation (Ballas N, et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron. 31:353-365, 2001). LSD1 erases the methyl groups from mono- and di-methyl Lys4 of histone H3, which is a well-characterized gene activation mark. The enzyme is an interesting target for epigenetic drugs as suggested by its overexpression in solid tumors (Schulte J H, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res 69:2065-2071, 2009), its role in various differentiation processes (Hu X, et al. LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc Natl Acad Sci USA 106:10141-10146, 2009), its involvement in herpes virus infection (Gu H, Roizman B. Engagement of the lysine-specific demethylase/HDAC1/CoREST/REST complex by herpes simplex virus 1. J Virol 83:4376-4385, 2009), and its association to HDAC1, a validated drug-target. LSD2 is a more recently discovered demethylase which, like LSD1, displays a strict specificity for mono- and di-methylated Lys4 of H3. However, the biology of LSD2, which remains only partly characterized, proposed to differ from that of LSD1 since LSD2 does not bind CoREST and it has not been found so-far in any LSD1-containing protein complex (Karytinos A, et al. A novel mammalian flavin-dependent histone demethylase. J Biol Chem 284:17775-17782, 2009).
LSD1 and LSD2 are multi-domain proteins which share a similar catalytic domain (45% sequence identity) that is structurally homologous with the monoamine oxidases (MAOs) A and B. Tranylcypromine, (±)-trans-2-phenylcyclopropyl-1-amine (tPCPA), a MAO inhibitor used as antidepressive drug, is also able to inhibit LSD1 (Schmidt D M, McCafferty D G. trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46:4408-4416, 2007).

Gooden et at (Bioorg. Med. Chem. Lett. 18, 3047-3051, 2008) describes a synthetic route to substituted trans-2-arylcyclopropylamines as inhibitors of LSD1 and MAOs. These derivatives are more than 10 fold more efficient in inhibiting MAO A and B than LSD1.
Culhane et al (J. Am. Chem. Soc. 132, 3164-3176, 2010) relates to the hydrazine containing MAO inhibitor phenelzine as a small molecule LSD1 inhibitors.
WO 2010011845 describes a method of treating a viral infection of a host, by administering to the host an inhibitor of the protein LSD1 (an RNAi molecule) and/or a monoamine oxidase inhibitor, e.g. tranylcypromine.
EP 1693062 relates to the use of at least one siRNA (“short interfering RNA”) and at least one anti-LSD1 antibody, also in combination with a monoamine oxidase inhibitor, e.g. tranylcypromine, for modulating the activity of LSD1 and controlling the androgen receptor-dependent gene expression.
WO 2010/043721, WO 2010/084160 and WO 2010/143582, W02011/035941 which were published after the priority date of the present application, disclose phenylcyclopropylamine derivatives capable of selectively inhibiting the function of LSD1. None of disclosed compounds are within the instant invention.
Hence there is a need to identify small molecules as potent and selective inhibitors of the LSD1 and/or LSD2 histone demethylase, which are useful in the prevention or therapy of diseases and conditions associated with the activity of the histone demethylases.
The compounds of the present invention are small molecules endowed with potent histone demethylases inhibitory activity, which are useful in the treatment of a variety of diseases in which deregulation of gene transcription, cell differentiation and proliferation is observed, e.g. tumors, viral infections.